Synaptic accumulation of misfolded proteins and neurodegeneration Age-dependent neurodegenerative diseases, such as Parkinson?s (PD), Alzheimer?s (AD), and Huntington?s diseases (HD), share the major features of late onset and selective neurodegeneration. These diseases are characterized by age-dependent accumulation of misfolded proteins in synapses and synaptic dysfunction, which are early pathological events. Unlike other neurodegenerative diseases that are mainly sporadic, HD is a monogenic disorder caused by expansion of a CAG repeat in exon 1 of the HD gene, which encodes a polyglutamine repeat in the N-terminal region of huntingtin (Htt). Because of its well-defined genetic mutation and neuropathology, HD makes an ideal system for investigating the pathogenesis of age-dependent neurodegenerative diseases. Moreover, numerous studies have shown that mutant Htt can impair synaptic function, an early neuropathological event that is also common in many other age-dependent neurological disorders. Understanding the mechanism behind the synaptic accumulation of misfolded proteins is important to unravel the pathogenesis of age-dependent neurodegenerative diseases and develop treatments for the early neuropathology that occurs in them. Our recent studies suggest that the age-related increase in the ubiquitin-conjugating enzyme UBE2N in synaptosomes may contribute to the impaired synaptic clearance of mutant Htt in aged brains. We hypothesize that the synaptic accumulation of misfolded proteins is protein context dependent and that inhibiting UBE2N expression may alleviate the synaptic accumulation and toxicity of misfolded proteins. To test these hypotheses, we will use CRISPR/Cas9 to generate new mouse models that delete exon1 of mouse htt or express truncated mutant Htt at the endogenous level. These new knock-in mouse models will allow us to explore the protein context-dependent effects on the synaptic accumulation and toxicity of misfolded proteins. We will also selectively suppress UBE2N in HD knock-in, transgenic alpha- synuclein, and tau mouse brains to examine whether such inhibition can alleviate the synaptic accumulation of misfolded proteins and their toxicity. Our studies aim to help develop effective strategies for treating the early neuropathology of age-related neurodegenerative disorders.